CCR5Δ32 Genotype Leads to a Th2 Type Directed Immune Response in ESRD Patients

Friso L H Muntinghe,Gerjan Navis,Minke G Huitema,Jeffrey Damman,Simon P M Lems,Johanna Westra,Bouke G Hepkema,Marc A Seelen,Wayel H Abdulahad

doi:10.1371/journal.pone.0031257

Friso L H Muntinghe, Gerjan Navis + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0031257

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Journal: PloS one	Publication Date: Feb 13, 2012
Citations: 34	License type: CC BY 4.0

Affiliation: University Medical Center Groningen

Abstract

BackgroundIn patients with end stage renal disease (ESRD) we observed protection from inflammation-associated mortality in CCR5Δ32 carriers, leading to CCR5 deficiency, suggesting impact of CCR5Δ32 on inflammatory processes. Animal studies have shown that CCR5 deficiency is associated with a more pronounced Th2 type immune response, suggesting that in human CCR5Δ32 carriers the immune response may be more Th2 type directed. So, in the present study we determined the Th1-Th2 type directed immune response in ESRD patients carrying and not carrying the CCR5Δ32 genetic variant after stimulation.Methodology/Principal FindingsWe tested this hypothesis by determining the levels of IFN-γ and IL-4 and the distribution of Th1, Th2 and Th17 directed circulating CD4+ and CD8+ T cells and regulatory T cells (Tregs) after stimulation in ESRD patients with (n = 10) and without (n = 9) the CCR5Δ32 genotype. The extracellular levels of IFN-γ and IL-4 did not differ between CCR5Δ32 carriers and non carriers. However, based on their intracellular cytokine profile the percentages IL-4 secreting CD4+ and CD8+ T cells carrying the CCR5Δ32 genotype were significantly increased (p = 0.02, respectively p = 0.02) compared to non carriers, indicating a more Th2 type directed response. Based on their intracellular cytokine profile the percentages IFN-γ and IL-17 secreting T cells did not differ between carriers and non-carriers nor did the percentage Tregs, indicating that the Th1, Th17 and T regulatory response was not affected by the CCR5Δ32 genotype.Conclusions/SignificanceThis first, functional human study shows a more pronounced Th2 type immune response in CCR5Δ32 carriers compared to non carriers. These differences may be involved in the previously observed protection from inflammation-associated mortality in ESRD patients carrying CCR5Δ32.

Highlights

Genetic variability in the chemokine cascades could potentially influence disease outcomes by modifying inflammatory processes
Extracellular cytokines of type-1 and type-2 T cells To assess the functional capacity of the responding PBMCs the total amount of IFN-c and IL-4 after stimulation was determined
In the present study we demonstrate a skewing of circulating CD4+ and CD8+ T cells towards the Th2 phenotype based on their intracellular cytokine profile after stimulation in end stage renal disease (ESRD) patients carrying the CCR5D32 genotype

Summary

Introduction

Genetic variability in the chemokine cascades could potentially influence disease outcomes by modifying inflammatory processes. The CCR5D32 genetic variant is located on the chromosome 3p21 and consists of a 32-basepair deletion in the open reading frame. It effectively results in functional CCR5 deficiency by absence of CCR5 membrane expression [3]. We observed protection from inflammation-associated mortality in carriers of the deletion 32 allele in end stage renal disease (ESRD), suggesting impact of CCR5D32 on the inflammatory process of atherosclerosis [4]. In patients with end stage renal disease (ESRD) we observed protection from inflammation-associated mortality in CCR5D32 carriers, leading to CCR5 deficiency, suggesting impact of CCR5D32 on inflammatory processes. In the present study we determined the Th1-Th2 type directed immune response in ESRD patients carrying and not carrying the CCR5D32 genetic variant after stimulation

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